Cross Talk between the Cardiovascular and Nervous Systems:Neurotrophic Effects of Vascular Endothelial Growth Factor (VEGF) and Angiogenic Effects of Nerve Growth Factor (NGF)-Implications in Drug Development

Philip      Lazarovici; Cezary      Marcinkiewicz; Peter   I.   Lelkes

Abstract

Both blood vessels and nerves are guided to their tissue targets by "specific" growth factors such as vascular endothelial growth factor (VEGF) and nerve growth factor (NGF), originally discovered as growth factors specific for endothelial and neuronal cells, respectively. While the eminent role of VEGF in the formation of new blood vessels (angiogenesis) is unquestioned, recent studies indicate that VEGF also has direct effects on the nervous system in terms of neuronal growth, survival (neurotrophic), axonal outgrowth (neurotropic), and neuroprotection. Conversely, NGF, a neurotrophin that plays a crucial role in promoting neurotrophic and neurotropic effects in sympathetic neurons, has recently been identified as a novel angiogenic molecule exerting a variety of effects on endothelial cells and in the cardiovascular system in general. VEGF and NGF have also been implicated in both neurodegenerative and vascular diseases. The pleiotropic effects of these growth factors have raised interest in assessing their therapeutic potential. The challenge for the future is to unravel to what extent the effects of these growth factors are interrelated with regards to their angiogenic, and neurotrophic effects and how to design selective drugs interfering with their respective actions. Most biological actions of NGF and VEGF are mediated by their cognate receptor protein tyrosine kinases, tropomyosin related kinase (trkA for NGF) and kinase insert domain-containing receptor (KDR, VEGFR-2, flk-1 for VEGF), which activate a complex and integrated network of signaling pathways in neurons and endothelial cells. Two small molecules, K252a and SU-5416, which are antagonists of trkA and VEGFR-2, respectively, may serve as key tools in dissecting the role of NGF and VEGF in angiogenesis and neurogenesis. Development of selective drugs specific for the trkA and VEGFR-2 subtypes of receptors will provide new tools for the treatment of neurodegenerative diseases, such as Alzheimer ’ s and Parkinsons, as well as of numerous angiogenesis-dependent diseases, such as cancer, diabetes, and arthritis.

Keywords: NGF, VEGF, trkA, VEGFR-2, K252a, SU-5416, angiogenesis, neurotrophic, neuron, endothelial cell